U.S. patent number 10,983,132 [Application Number 15/773,998] was granted by the patent office on 2021-04-20 for method and product for testing response to oral glucose load.
This patent grant is currently assigned to NUTRITION DNA PTY LTD. The grantee listed for this patent is Nutrition DNA PTY LTD. Invention is credited to Ian Barabash, Nathan Givoni, Thomas P. Kralj, Felix Meiser.
United States Patent |
10,983,132 |
Barabash , et al. |
April 20, 2021 |
Method and product for testing response to oral glucose load
Abstract
A dosage form of glucose and a method of performing an oral
glucose tolerance test or challenge test on a patient are
disclosed. The dosage form of glucose may be a drinkable gel
formulation and include water, a primary gelling agent, and a pH
adjuster. The water, the primary gelling agent, and the pH adjuster
may be present in amounts which ensure proper hydration and a
formation of a firm gel with a bloom grade of at least 100, which
can be sheared to make it more fluid, such that it is a drinkable
gel.
Inventors: |
Barabash; Ian (Malvern,
AU), Givoni; Nathan (Caulfield Junction,
AU), Meiser; Felix (Parkville, AU), Kralj;
Thomas P. (Parkville, AU) |
Applicant: |
Name |
City |
State |
Country |
Type |
Nutrition DNA PTY LTD |
St. Kilda |
N/A |
AU |
|
|
Assignee: |
NUTRITION DNA PTY LTD
(N/A)
|
Family
ID: |
1000005500043 |
Appl.
No.: |
15/773,998 |
Filed: |
November 5, 2016 |
PCT
Filed: |
November 05, 2016 |
PCT No.: |
PCT/AU2016/051061 |
371(c)(1),(2),(4) Date: |
May 04, 2018 |
PCT
Pub. No.: |
WO2017/075672 |
PCT
Pub. Date: |
May 11, 2017 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20180321249 A1 |
Nov 8, 2018 |
|
Foreign Application Priority Data
|
|
|
|
|
Nov 6, 2015 [AU] |
|
|
2015904571 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/7004 (20130101); A61K 9/06 (20130101); A61K
9/0095 (20130101); G01N 33/66 (20130101); A61K
47/36 (20130101); G01N 2800/042 (20130101) |
Current International
Class: |
G01N
33/66 (20060101); A61K 9/00 (20060101); A61K
47/36 (20060101); A61K 31/7004 (20060101); A61K
9/06 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Searcy, R. L. et al., `Clinical Trials of a New Gelatin-Glucose
Meal for Tolerance Tests`, Current Therapeutic Research, Clinical
and Experimental. 1966, vol. 8, No. 2, pp. 41-47. cited by
applicant .
Seachy, R. L. et al., `Occult Glucose Intolerance: Incidence in a
General Population`, California Medicine. 1967, vol. 106, No. 5,
pp. 364-367. cited by applicant .
Anonymous, `Glucola and Gel-A-Dex for Oral Glucose Tolerance
Tests`, Medical Letter on Drugs and Therapeutics. 1966, vol. 8, No.
4, p. 16. cited by applicant .
Glucose products [retrieved from the intemet Jan. 17, 2017]:
<URL:
httlp://main.diabetes.org/dforg/pdfs/2015/2015-cg-glucose-products.pdf>-
;published Mar./Apr. 2015. X [p. 74, "Gels"]. cited by applicant
.
Dextrogel--Fast Acting Dextrose Gel [retrieved from the internet on
Jan. 11, 2017]: <URL: https://web.archive.org/web/20151
013181619/http://www.dextrogel.co.uk/index.html> published on
Oct. 13, 2015 as per Wayback Machine. cited by applicant .
Product Data Sheet (Rapilose gel) [retrieved from the internet Jan.
11, 2017]: <URL:
http://penlanhealthcare.com/uploads/s/Rapilose-Gel-Data-Sheet.pdf>
published Jul. 2011. cited by applicant .
Thickening Agents [retrieved from the intemet Jan. 11, 2017]:
<URL:httlps://en.wikipedia.org/w/index.php?title=Thickening_agent&oldi-
d=672715396> published Jul. 23, 2015. cited by applicant .
Supplementary European Search Report dated Jul. 10, 2019 related to
corresponding European Patent No. EP16861128. cited by applicant
.
K Holm: "The Relations Between Food Structure and Sweetness; A
Literature Review", Jan. 1, 2006, pp. 1-58. Retrieved from the
Internet: URL:
https://epo.summon.serialssolutions.com/2.0.0/1ink/0/eLvHCXMwY2BQSTNPMbGO-
SE3WtUxONNMIsUy21LUOTrXUTUmlsEgCHaGVAj6JKdLZJMTdPMjdxAexjxsYfNBF7sDOZn50Wa-
09UMQiK3ykvKsilOtijKtUjLLEnVNLIDILitoAaQZ2iGf4IrBTZCBxwVpQlulgSkIT4TBAxj2C-
kWwVWYKOKVQCmn5
-SkKkPNaS4tSFYBdeAWgiakloMJGwUohUSEHfsSxAmRHiSiDpptri LOHLsTm-AL.
cited by applicant .
Anonymous: "Handbook of Pharmaceutical Excipients", 2006,
Pharmaceutical Press, UK. cited by applicant.
|
Primary Examiner: Wecker; Jennifer
Attorney, Agent or Firm: Fishman Stewart PLLC
Claims
The invention claimed is:
1. A dosage form of glucose which is a drinkable gel formulation
comprising: 50 to 75 g of glucose; water; a primary gelling agent
that is an agar; and a pH adjuster; wherein said water, the primary
gelling agent, and the pH adjuster are present in amounts which are
configured to ensure proper hydration and a formation of a firm gel
with a bloom grade of at least 100, such that the firm gel is
sheared to make it more fluid, such that it is a drinkable gel.
2. The dosage form as claimed in claim 1, further comprising a
secondary gelling agent.
3. The dosage form as claimed in claim 1, further comprising a
preservative.
4. The dosage form as claimed in claim 1, wherein the bloom grade
is at least 140.
5. The dosage form as claimed in claim 1, wherein a pH of the
drinkable gel is between 4 and 6.
6. The dosage form as claimed in claim 1, wherein the drinkable gel
is packaged in a pouch including a spout such that the drinkable
gel can be extracted by sucking through the spout or squeezing
pouch or a combination thereof, so as to extract and drink
substantially all of the drinkable gel contained in the pouch.
7. The dosage form as claimed in claim 6, wherein the drinkable gel
contains 75 g of glucose.
8. The dosage form as claimed in claim 1, wherein said water is
contained in an amount of from 100 m1 to 150 m1.
9. The dosage form as claimed in claim 1, wherein the pH adjuster
is acidic.
10. The dosage form as claimed in claim 2, wherein the primary
gelling agent and the secondary gelling agent are contained in an
effective amount such that the bloom grade is at least 140.
11. The dosage form as claimed in claim 2, wherein the secondary
gelling agent is locust bean gum and a pH of the drinkable gel is
between 4 and 6.
12. The dosage form as claimed in claim 11, further comprising a
preservative that is potassium sorbate.
13. A method of performing an oral glucose tolerance test or
challenge test on a patient, the method comprising the steps of: i)
administering to a patient a dosage form of glucose, the dosage
form of glucose composed of a drinkable gel formulation including
water, a primary gelling agent that is an agar, and a pH adjuster,
wherein said water, the primary gelling agent, and the pH adjuster
are present in amounts which ensure proper hydration and a
formation of a firm gel with a bloom grade of at least 100, such
that the firm gel is sheared to make it more fluid, such that it is
a drinkable gel; ii) taking blood samples at one or more defined
time points relative to the step of administering; and iii)
determining a plasma glucose level at the one or more defines time
points.
14. The method as claimed in claim 13, wherein the patient is an
overnight fasted patient.
15. The method as claimed in claim 14, wherein the one or more
defined time points are zero hours and 2 hours after administering
the dosage.
16. The method as claimed in claim 14, wherein the dosage form of
glucose comprises 75 g of glucose.
17. The method as claimed in claim 13, wherein the patient is a
non-fasted pregnant patient, and wherein the defined time point is
1 hour after administering the dosage.
18. The method as claimed in claim 17, wherein the dosage form of
glucose comprises 50 g of glucose.
19. The method as claimed in claim 13, wherein the primary gelling
agent is provided in an effective amount such that the bloom grade
is at least 140.
20. A dosage form of glucose which is a drinkable gel formulation
comprising: 50 to 75 g of glucose; water; a primary gelling agent
that is an agar; a secondary gelling agent; a pH adjuster; wherein
said water, the primary gelling agent, and the pH adjuster are
present in amounts which are configured to ensure proper hydration
and formation of a firm gel, such that the firm gel is sheared to
make it more fluid, such that it is a drinkable gel; and wherein
the primary gelling agent and the secondary gelling agent are
contained in an effective amount such that a bloom grade of the
drinkable gel is at least 140, and wherein a pH of the drinkable
gel is between 4 and 6.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to International Application
PCT/AU2016/051061 filed on Nov. 5, 2016 and to Australian
Application AU 2015904571 filed on Nov. 6, 2015, the contents each
of which are hereby incorporated by reference in their
entirety.
TECHNICAL FIELD
The present invention relates to tests in humans designed to
determine a response to ingestion of an oral glucose load, such as
the oral glucose tolerance test (OGTT) and the oral glucose
challenge test (OGCT).
BACKGROUND
The oral glucose tolerance test (OGTT) has been used for many years
to determine how quickly glucose is cleared from the blood. This
test may be used to detect diabetes, insulin resistance or other
disorders of glucose metabolism.
The general procedure of the OGTT is that at zero time and blood
sample is taken from an overnight-fasted patient, and the patient
is then given a measured dose of glucose solution to drink within a
short time period, typically five minutes. Typically, the dose is
75 g of glucose in all adults, or alternatively 1.75 g of glucose
kilogram body weight to a maximum of 75 g as practised in the
USA.
Blood sample measurements are then taken at different time
intervals after the dose. For simple diabetes screening, the most
important sample is at two hours after dose, and in a simple form
of the test only the 0 and 2 hour samples may be collected and
analysed for glucose concentration.
Zero time plasma glucose (measured before the OGTT begins) should
be below 6.1 mmol/L (110 mg/dL). Fasting levels between 6.1 and 7.0
mmol/L (110 and 125 mg/dL) are borderline ("impaired fasting
glycaemia"), and fasting levels repeatedly at or above 7.0 mmol/L
(126 mg/dL) are diagnostic of diabetes. A 2 hour OGTT glucose level
below 7.8 mmol/L (140 mg/dL) is normal, whereas higher glucose
levels indicate hyperglycemia. Blood plasma glucose between 7.8
mmol/L (140 mg/dL) and 11.1 mmol/L (200 mg/dL) indicate "impaired
glucose tolerance", and levels above 11.1 mmol/L (200 mg/dL) at 2
hours confirms a diagnosis of diabetes.
The oral glucose challenge test (OGCT) is a simpler version of the
OGTT which is used to check pregnant women for signs of gestation
of diabetes. It is performed in a non-fasted state and involves the
ingestion of 50 g of glucose rather than 75 g, with a reading after
one hour.
Many patients find the oral glucose drink containing 50 g or 75 g
of glucose very unpleasant, and many patients suffer nausea,
bloating, gastrointestinal pain or vomiting.
Some hospitals suggest that the patients take instead a number of
jellybeans in the belief that the carbohydrate provided by the
various sugars in jellybeans can be equivalent to an oral glucose
liquid load, although the particular number and brand of jellybeans
that might be equivalent has not been established. Jellybeans
typically contain 53 percent sucrose, 14 percent dextrose
(glucose), six percent cornstarch, and 18 percent higher
saccharides. In 2010 an article appearing in CAP Today by Kevin F.
Foley, PhD, and Shirley L. Welch, PhD concluded that "Those who are
using this "off-label" method don't appear to be consistent in the
number or brand of jelly beans used. Preanalytical testing issues
are, as CLIA mandates, under the purview of laboratory directors
and managers. In our opinion, the advantages of jelly bean
administration do not outweigh the risks of a false-negative screen
in an expectant mother. Until this approach has been validated, the
jelly beans should stay in the Easter basket and out of the
clinics."
The fact that an approach as non-standard and non-controllable as
jellybeans has become common place is testament to the practical
problem of organoleptic challenge faced by practitioners using the
OGTT when faced with the many patients who find ingestion of the
liquid glucose difficult. There is therefore a need to provide an
improved product and method for administering a standardised
glucose load.
The inventors have conceived an improved method and product which
can maintain the accuracy of the liquid glucose method while
avoiding its disadvantages.
SUMMARY
The inventors have realised that a substantial component of the
unpleasantness of the current glucose formulation and resulted
nausea resides in the strong sweet taste as the formulation is
ingested, and that this can be ameliorated without resort to solid
dosage forms.
Therefore in accordance with a broad aspect of the invention there
is provided a method of performing an oral glucose tolerance or
challenge test on a patient, the method comprising the steps
of:
(i) administering to the patient a defined amount of a drinkable
gel formulation containing glucose as the dominant
carbohydrate;
(ii) measuring a blood glucose concentration of the patient at one
or more defined time points relative to the step of administering;
and
(iii) determining the patient's glucose tolerance condition from
the blood glucose concentrations at the defined time point(s).
In one embodiment, the step of determining comprises using a
standardised function which has been calibrated by a controlled
clinical trial comparing blood glucose concentrations in patients
administered a standardised liquid glucose formulation and blood
glucose concentrations in patients administered the drinkable gel
formulation or an equivalent thereof. The controlled clinical trial
may have compared blood glucose concentrations at two hours post
dose in patients administered with one or more doses of glucose in
the standard liquid glucose formulation, with blood glucose
concentrations at two hours post dose in patients administered the
one or more doses of glucose provided in the drinkable gel
formulation or an equivalent thereof.
In one embodiment, the drinkable gel formulation contains as
carbohydrate substantially pure glucose.
In one embodiment, the drinkable gel formulation comprises an
effective amount of a gelling agent to result in a Bloom grade of
at least 100 g, preferably at least 140 g, further preferably at
least 160 g, even further preferably at least 180 g and most
preferably at least 200 g.
In one embodiment, the gelling agent comprises agar.
In one embodiment, the gelling agent comprises agar and locust bean
gum.
In one embodiment, the drinkable gel formulation comprises a
solution of glucose in water together with a gelling agent.
In one embodiment, the drinkable gel formulation comprises an
amount of glucose suitable for an oral glucose challenge test and
is provided in a plastic pouch.
In accordance with a second broad aspect of the invention there is
provided a dosage form of glucose formulated in a drinkable gel,
provided in an amount of glucose adapted for carrying out one oral
glucose tolerance or challenge test on one patient.
In one embodiment, the dosage form is contained in a plastic
pouch.
In one embodiment, the amount is 50 gram or 75 gram of glucose.
In one embodiment, the drinkable gel formulation comprises an
effective amount of a gelling agent to result in a Bloom grade of
the drinkable gel formulation of at least 100 g, more preferably
140 g, 160 g, 180 g and most preferably at least 200 g.
In one embodiment, the drinkable gel formulation comprises a
gelling agent consisting primarily of agar.
In one embodiment, the drinkable gel formulation comprises agar as
a primary gelling agent, locust bean gum as a secondary gelling
agent, and a pH of the drinkable gel formulation is adjusted having
regard to balancing ease of consumption and palatability.
In one embodiment, a pH of the drinkable gel formulation is less
than 6.0 and greater than 4.0.
BRIEF DESCRIPTION OF THE DRAWINGS
The FIGURE shows a dispensing dosage form according to an
example.
DETAILED DESCRIPTION OF THE DRAWINGS
Embodiments of the current invention will now be described.
Preparation of Gel Formulation
This embodiment relates to the glucose tolerance test and aims to
produce an equivalent dose of glucose to the standard glucose
solution, which is 75 g of glucose dissolved in 150 ml water, with
similar rapid blood-sugar uptake from the gut, but in a modified
gel formulation that reduces the organoleptic challenge by
providing a sufficient degree of reduction in the sweetness,
essentially partially masking to minimise this taste which
otherwise can significantly reduce compliance.
From a series of prototype compacts, granules, gels and chilled
formats, a halal, kosher and vegan friendly gel was deemed to be an
optimal candidate.
The composition of the formulation is provided in table 1 below
TABLE-US-00001 TABLE 1 composition of example formulation
Ingredient Amount Function Water 100 ml Solvent Glucose 75 g Active
ingredient Agar 0.75 g Primary gelling agent Locust bean gum 0.25 g
Secondary gelling agent Potassium sorbate 0.14 g Preservative HCl
As required PH adjustment
Experiments performed adjustment of the solution pH using 0.1M HCl
to approximately 5.6 or 4.3 for purposes of comparison.
The production process of the gel involved the following: Water is
stirred dissolving the glucose, preservative and HCl in the water.
For addition of the gelling agents, the solution must be stirred
and heated until boiling requiring gradual adding of the gelling
agents to allow satisfactory dispersing, and kept at boiling for
between 4-5 minutes. This is needed to ensure proper hydration of
the agar and the formation of a firm gel. However, the shortest
suitable heating is advantageous in that it reduces the water loss
from evaporation--which may lead to product variability. After
heating this solution can be poured hot into desired container
(such as pouch 1 described below) and allowed to cool and then
gel.
Gel strength varies with production process, with water content,
with gel agent nature and concentration and with pH. Gel can also
be sheared to make it more fluid. However, a softer drinkable gel
such as produced under these circumstances, allows more
weeping/leakage of free, non-gelled solution of glucose. This leads
to a sweeter product taste than a firm gel, and so the invention is
best implemented with a compromise between softness to provide a
drinkability and firmness to minimise unpleasant sweetness.
Gel strength can be quantified by measurement of the Bloom grade,
as is known in the art. The Bloom grade is defined as the amount of
force required to depress a probe 4 mm into a gelatin gel surface.
The standard test involves preparing a 6.67% w/w gelatin gel which
is heated and mixed and left to set at room temperature and
conditioned at 10 degrees for 16 hours. In this example, a
cylindrical probe was taped to a force gauge which is held by a
scaffold to be able to move a beaker containing the test gel
towards the probe. A ruler was employed to measure out 4 mm
deflection of the gel. 3 standard solutions of gelatin gels were
prepared to measure the baseline Bloom grade of the apparatus.
These 3 standards produced a Bloom grade of 156 g, which is
slightly lower than the expected published 180 g Bloom grade for
this as a standard.
The two formulations above produced the resultant raw deflection
values of 199 g at pH 5.6, and 181 g at pH 4.3. Taking into account
the discrepancy with the standards and the published Bloom grade of
180 g, the true Bloom grade of the formulations may be somewhat
higher than the raw measured values. It is expected that a Bloom
grade greater than 100 g is preferable to produce a gel which
reduces sweetness. More preferably, the Bloom grade should be
greater than 140 g, further preferably over 160 g, further
preferably over 180 g and most preferably over 200 g. Such
adjustments can be produced by changing the concentration of
gelling agents and pH.
It was found in taste testing that the pH 4.3 formulation was
preferable, being palatable and easy to consume. The pH 5.6
formulation was equally palatable but was firmer and more difficult
to consume. Observations of thinner formulations obtained by
reducing pH below 4.3 produced a formulation which was less firm
and noticeably sweeter and less palatable.
The potassium sorbate used in the above prototype examples is used
as a proof of concept that a preservative can be included as a mild
acidic pH with no noticeable effect on the gel properties. However,
at pH 5.6 potassium sorbate may not be sufficiently active as a
preservative and alternative preservatives may be appropriate at pH
5.6.
From observation of short-term storage the above prototypes, gel
formulation appears physically stable provided the container is
kept sealed to prevent dehydration.
Dispensing Dosage Form
Now referring to the FIGURE, a dispensing dosage form appropriate
for a single dose in a single patient comprises a plastic pouch 1
containing a standardised amount of the gel formulation 2,
typically 50 g or 75 g. Pouch 1 is formed from plastic layers
sealed together around an edge 3 incorporating a filling and
dispensing aperture comprising plug 4, spout 5 and cap 6. Pouch 1
is filled with formulation through mouthpiece 5 and secured with
cap 6 which may be provided with a frangible seal. Pouch 1 may
filled in advance in a manufacturing facility ensuring accurate
dispensing.
Usage
In use, the patient removes cap 6 and drinks the gel formulation 2,
extracting the gel formulation 2 by sucking through spout 5 or
squeezing pouch 1 or a combination thereof so as to extract and
drink substantially all of the contents of pouch 1 in a short a
time as reasonably practicable to establish a clear time point of
administration, as in the standard test. The glucose tolerance or
challenge test is performed as normal, measuring blood glucose
concentrations at one or more defined time points after the time of
administration.
Calibration
The controlled trial which can be performed in order to determine
the standardised function can have a number of designs. The trial
on a group of patients should compare measurements of blood glucose
at defined time points after administration of the drinkable gel
formulation with measurements of blood glucose at defined time
points after administration of a standard glucose drink. Ideally
but not necessarily, the doses of the two different formulations
are the same and the time points at which measurements are made are
the same. Also ideally but not necessarily, the same patients are
used to compare each dose on different occasions, for which a
crossover design may be appropriate. Also ideally but not
necessarily, more than one dose of each formulation is given.
From the clinical data generated a calibration is then possible to
relate blood glucose taken with the drinkable gel formulation to a
corresponding blood glucose according to the conventional liquid
glucose drink formulation protocol. There are of course, as the
person skilled in the art of clinical trial design will appreciate,
many different ways of achieving the aim of calibration, which is
to provide a function determining the patient's glucose tolerance
condition from the blood glucose concentrations at the defined time
point(s) using the drinkable gel formulation. Ideally, the clinical
data confirms that the same function is appropriate for the
drinkable gel formulation as is already known in the prior art for
the liquid formulation, such that the same values of blood glucose
values are relevant to the same interpretations of blood glucose
tolerance condition as is used for the liquid formulation. In
reality, there may be significant differences between the two
formulations observed in which case a calibration function can be
determined to translate the blood glucose measurements under the
new formulation to equivalent blood glucose measurements under the
liquid glucose drink formulation.
Persons skilled in the art will appreciate that many variations may
be made to the invention without departing from the scope of the
invention.
For example, the calibration clinical trial described above in an
embodiment is not required in a broadest aspect of the invention,
and when required as defined in one or more of the claims herein,
the calibration clinical trial may have been performed by another
party of the drinkable gel formulation or an equivalent drinkable
gel formulation.
Further, a person skilled in the art will understand that
adjustments can be made to the gel properties by various means,
such as modifying the nature and proportions of gelling agents,
concentration and pH of the formulation. Such variations are within
the broadest scope of the invention which extends to any drinkable
gel formulation.
In the claims which follow and in the preceding description of the
invention, except where the context requires otherwise due to
express language or necessary implication, the word "comprise" or
variations such as "comprises" or "comprising" is used in an
inclusive sense, i.e. to specify the presence of the stated
features but not to preclude the presence or addition of further
features in various embodiments of the invention. Further, any
method steps recited in the claims are not necessarily intended to
be performed temporally in the sequence written, or to be performed
without pause once started, unless the context requires it.
It is to be understood that, if any prior art publication is
referred to herein, such reference does not constitute an admission
that the publication forms a part of the common general knowledge
in the art, in Australia or any other country.
* * * * *
References